Preterm birth is the leading cause of perinatal mortality and is associated with long-term adverse health consequences for surviving infants. No effective means for prevention of prematurity currently exists, and with preterm birth rates rising in the U.S. and worldwide, investigating possible causal mechanisms is a global public health priority. A recent Institute of Medicine Report notes that air pollution exposure may be a significant cause of prematurity, but most published studies are based on population birth registries and lack the individual, clinical data needed to elucidate possible biological mechanisms mediating these epidemiological associations. This proposed work presents a unique opportunity to study those mechanisms in a new cohort of 800 pregnant women residing in diverse regions of Mexico City, a mega-city with high air pollution levels. We will advance understanding of prematurity by investigating how air pollution and inflammation may act together to influence the outcome of pregnancy, and whether certain periods of gestation represent critical time windows and opportunities for preventive interventions, both clinical and environmental. We will obtain biomarkers relevant to inflammation and preterm delivery (IL-1, IL-1r, IL-6, IL-8, IL-10, TNF-) in cervico-vaginal exudate provided by participants monthly during their pregnancies, along with information on infections, health history, clinical characteristics, diet and time-activity patterns. We will use state-of-the-art exposure assessment techniques to evaluate spatial and temporal variability in air pollution exposure using data from the Mexico City Metropolitan Area (MCMA) air quality monitoring network (PM2.5, PM10, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide), matched to locations of participants' homes. At birth, DNA samples from mother and infant will be used to type three genetic cytokine polymorphisms (TNF-, IL-1, IL- 1r) that have been associated with enhanced risk of preterm birth. We will evaluate whether ambient pollution is associated with preterm birth, controlling for other risk factors; whether they are associated with cytokines during pregnancy, and which time windows are most relevant. We will examine effect modification by intake of antioxidant vitamins (E and C) and cytokine polymorphisms. Finally, we will complement this epidemiological study with a parallel toxicology in-vitro study which will involve collecting and characterizing air pollution particle samples (PM10 and PM2.5) on a monthly basis from five zones in MCMA and exposing a monocytic cell line (J774A.1) to evaluate expression of the same cytokines. Any coherence between the human and in vitro evidence for a mechanistic association between pollution and these mediating molecules will guide future studies. This multi-disciplinary, global health collaboration will evaluate potential environmental and clinical determinants of preterm delivery, with the goal of developing unique knowledge with far-reaching prevention implications. Project Narrative Relevance to public health: This research investigates how air pollution influences the risk for preterm birth, with a focus on elucidating the potential role for inflammatory mechanisms. The goal is to develop knowledge to support 1) policy-makers who set and enforce health-protective air pollution standards; 2) scientists involved in multi-disciplinary studies to understand environmental contributions to infant health, and 3) clinicians interested in prevention of preterm birth.